Chaperone-Mediated Protein Homeostasis in Neurodegenerative Diseases

Protein homeostasis or proteostasis is fundamental to neuronal health, relying upon molecular chaperones and their co-chaperones to guide folding, prevent misfolding and facilitate the clearance of aberrant proteins. In neurodegenerative conditions such as Alzheimer’s, Parkinson’s and Huntington’s diseases, the failure of this chaperone network contributes to accumulation of amyloid-β peptides, tau tangles, α-synuclein inclusions and polyglutamine aggregates. Chaperone systems—including heat shock proteins Hsp70 and Hsp90—recognise non-native polypeptides, escort them towards refolding or target them for degradation via ubiquitin–proteasome and autophagic pathways. Co-chaperones fine-tune this machinery by regulating ATPase cycles, client specificity and decision points between refolding and proteolysis. Age-related decline or stress-induced dysfunction of these factors can tip the balance towards proteotoxic stress, triggering synaptic impairment, mitochondrial dysfunction and neuroinflammation. Emerging evidence highlights bidirectional interplay between chaperone networks and innate immunity, revealing that chaperones not only safeguard proteostasis but also modulate immune signalling. Therapeutic strategies that restore chaperone capacity—through small-molecule modulators, upregulation of heat shock response or targeted disruption of pathogenic co-chaperone interactions—hold promise for slowing disease progression and enhancing neuronal resilience.

Research from Nature Portfolio

A recent transcriptomic study of Alzheimer’s patients and model mice has uncovered immunogenic cell death-related signatures intersecting with proteostasis pathways. By analysing differentially expressed genes in patient samples, researchers identified hub genes including HSP90AA1 alongside P2RX7, implicating elevated Hsp90 expression in tau hyperphosphorylation and neuroinflammatory cascades. Integration of immune-gene enrichment and validation in transgenic mice underscored how aberrant chaperone expression drives cytokine production and lipid-metabolism dysregulation. These findings provide a gene-level framework linking chaperone machinery with immune activation, suggesting that normalising Hsp90 levels may rebalance both proteostasis and inflammatory responses in Alzheimer’s disease.

Chaperone-Mediated Protein Homeostasis in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in chaperone-mediated protein homeostasis in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Proteostasis: The cellular network of pathways that maintains the steady-state of the proteome through synthesis, folding, trafficking and degradation.

Molecular chaperone: A specialised protein that assists the correct folding of other polypeptides and prevents aberrant aggregation.

Co-chaperone: A regulatory protein that modulates chaperone activity, client specificity or the decision between refolding and degradation.

Immune cell infiltration: The migration of immune cells into neural tissue, which can be driven by proteostasis failure and contribute to neuroinflammation.

Hyperphosphorylation: The excessive addition of phosphate groups to proteins such as tau, often leading to toxic oligomer formation and neurofibrillary tangles.

References

1. Protection against Aβ-induced neuronal damage by KU-32: PDHK1 inhibition as important target. Frontiers in Aging Neuroscience (2023).
2. The Crystal Structure of the Hsp90-LA1011 Complex and the Mechanism by Which LA1011 May Improve the Prognosis of Alzheimer’s Disease. Biomolecules (2023).
3. Identification of immunogenic cell death-related genes involved in Alzheimer’s disease. Scientific Reports (2024).
4. The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases. Frontiers in Neuroscience (2017).